Work

Activation of the aryl hydrocarbon receptor relieves acute pancreatitis via the RBX1/HSF1 pathway

Year: 2025

Type: article

Abstract: BACKGROUND: Acute pancreatitis (AP) represents one of the most prevalent acute gastrointestinal disorders. Research has indicated a significant correlation between aryl hydrocarbon receptor (AhR) signaling and pancreatic injury associated with AP. Nevertheless, the specific role of AhR signaling in tight junction injury induced by AP remains to be fully understood. METHODS: An experimental model of severe AP was established through repeated cerulein injections in conjunction with a single LPS injection. We evaluated pancreatic injury by quantifying serum amylase activity, LDH levels, pancreatic MPO levels, histopathological changes, tight junction protein expression, and the infiltration and polarization of macrophages. The regulatory interactions between AhR and HSF1 were analyzed through experimental validation and predictions derived from the BioGRID and Ubibrowser databases. RESULTS: AhR exhibited low expression and a negative correlation with the M1 polarization of pancreatic resident macrophages (PRM). In primary acinar cells treated with cerulein, AhR enhanced the activation of HSF1 signaling and mitigated the impairment of tight junction integrity. Conditioned medium from primary acinar cells overexpressing AhR resulted in the M2 polarization of PRM. RBX1 was identified as a potential mediator of the interaction between AhR and HSF1. RBX1 was found to facilitate HSF1 ubiquitination through its binding to HSF1, thereby promoting its degradation. Finally, AhR overexpression reduced cerulein/LPS-induced damage to pancreatic tight junction integrity in AP mice, while triptolide inhibited the therapeutic effects. CONCLUSION: AhR facilitates the ubiquitination modification of HSF1 through its interaction with RBX1. This results in the suppression of HSF1 expression and activation, thereby mitigating cerulein/LPS-induced damage to pancreatic tight junctions in AP mice CLINICAL TRIAL NUMBER: Not applicable.

Source: Journal of Inflammation

DOI: 10.1186/s12950-025-00481-7

Authors: Yu Fang, Chuanhai Zhang, Jihai Yu, Xiayong Shen

Institution: University of Science and Technology of China

Language: English

Topic: Pancreatitis Pathology and Treatment

Subfield: Surgery

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,190